Mitochondrial dysfunction underlies cortical atrophy in prodromal synucleinopathies

Abstract

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal synucleinopathy characterized by several changes including brain atrophy. The mechanisms underlying atrophy in iRBD are poorly understood. Here, we performed imaging transcriptomics and comprehensive spatial mapping in a multicentric cohort of 171 polysomnography-confirmed iRBD patients and 238 controls with T1-weighted MRI to investigate the gene expression patterns and the specific neurotransmitter, functional, cytoarchitectonic, and cognitive brain systems associated with cortical thinning in iRBD. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the thinning occurring in iRBD. Moreover, we demonstrated that thinning was constrained by the brain's connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with thickness, changes in cortical surface area related to distinct gene and spatial mapping patterns. This study demonstrates that the development of atrophy in synucleinopathies is constrained by specific genes and networks.

Brain MRI Biomarkers in Isolated Rapid Eye Movement Sleep Behavior Disorder: Where Are We? A Systematic Review

“…The locus coeruleus had no significant neuronal loss and gliosis but did have many Lewy bodies and Lewy neurites [20]. More recently, a large multicentric study found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to cortical thinning occurring in iRBD [21].…”

“…With regard to cortical GM, most of the studies reported decreased volume or thinning (Figure 2) in the frontal cortex [21,22,[24][25][26][27][28][29] in iRBD compared to healthy subjects. Also, the posterior temporal, parietal [29,47], dorsolateral prefrontal, orbitofrontal, occipital cortices [29,47,48] the superior frontal sulcus [25], the right superior frontal sulcus [27], and the dorsolateral primary motor cortex in the right hemisphere [22] were thinner or with a reduced volume.…”

“…Using structural and functional neighborhood analyses, a study demonstrated that cortical thinning was constrained by the brain's structural (and functional) connectome and that it mapped onto specific networks involved in motor and planning functions [21].…”

“…In iRBD, the most reported resting state fMRI (rsfMRI) result was a reduced nigrostriato-thalamo-pallidal inter-and intra-hemispheric connectivity [21,[40][41][42][43]63,[85][86][87][88].…”

“…Decreased volume in the frontal cortex [21,25], dorsolateral prefrontal, occipital cortices [47,48] • At baseline, a Dementia with Lewy Body-pattern was significantly higher in dementia-first than in parkinsonism-first converters [30,31,47]: thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices…”